Huntington's Disease (HD) is a progressive neurodegenerative dominant genetic disorder. The pathological state in HD can arise from a condition where neuronal metabolic requirements cannot be supplied by the proximal glial cells or where glial metabolic changes cannot be accommodated by the glutamergic and GABAergic neurons. These studies are proposed to help understand the mechanisms of cell degeneration in HD brains. The intent is (1), to characterize one or more biochemical alterations specific to HD in cultured HD skin fibroblast and (2), to determine the chromosomal assignment for the putative biochemical marker, Glus. Previous results indicate that increased sensitivity to glutamic acid and an abnormal synthesis of gamma-aminobutyric acid by glutamic acid decarboxylase are biochemical lesions found in cultured HD cells. HD cells, containing the Glus marker, will be fused with HGPRT rodent cells forming human-rodent hybrid clones. Analysis and correlation of the biochemical and genetic properties of the hybrid clones will be done. The biochemical characteristics of the Glus phenotype will be determined with respect to the enzymes involved in glutamate: glutamine interconversion, glutaminase and glutamine synthetase. Glutamic acid decarboxylase will be isolated from HD and control fibroblasts and the enzyme:membrane association analyzed by detergent effectiveness and reconstitution. A practical consequence of this work may be improved genetic counseling, prenatal diagnosis of HD and improved therapeutic approaches to the disease.